Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA288429 | ENA |
REPOSITORIES: ENA
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Project description:The biological functions of histone demethylases Jmjd3 and Utx remain poorly understood. We assessed such functions in developing T cells, using conditional (CD4-Cre-mediated) gene disruption, by inactivating Kdm6a and Kdm6b, respectively encoding Utx and Jmjd3, in immature CD4+CD8+ thymocytes. We compared microarray gene expression in mature (Va2hi CD24lo) mutant and wild-type CD4+CD8- thymocytes carrying the OT-II TCR transgene. We show that Jmjd3 and Utx redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress. Mature (Va2hi CD24lo) CD4 thymocytes were sorted from freshly prepared single-cell suspensions OT-II TCR transgenic thymocytes deficient for Utx and Jmjd3 (dKO, CD4-Cre conditional deletion of floxed Kdm6a and Kdm6b alleles), and from Cre-negative controls (wild-type). Total RNA was extracted from sorted thymocytes using the RNeasy Plus Mini Kit (Qiagen) and processed for microarray analyses (Affymetrix Mouse Exon 1.0 ST array) at the NCI microarray facility, following the manufacturer’s recommendation. Data is generated from 3 replicates from each experiment.
2015-09-17 | E-GEOD-70363 | biostudies-arrayexpress
Project description:The biological functions of histone demethylases Jmjd3 and Utx remain poorly understood. We assessed such functions in developing T cells, using conditional (CD4-Cre-mediated) gene disruption, by inactivating Kdm6a and Kdm6b, respectively encoding Utx and Jmjd3, in immature CD4+CD8+ thymocytes. We compared microarray gene expression in mature (Va2hi CD24lo) mutant and wild-type CD4+CD8- thymocytes carrying the OT-II TCR transgene. We show that Jmjd3 and Utx redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress.
2015-09-17 | GSE70363 | GEO
Project description:While histone H3 lysine 27 trimethylation (H3K27Me3) is associated with gene silencing, whether H3K27Me3 demethylation affects transcription and cell differentiation in vivo has remained elusive. To investigate this, we conditionally inactivated the two H3K27Me3 demethylases, Jmjd3 and Utx, in non-dividing intrathymic CD4+ T cell precursors. We show that both enzymes redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress. Floxed alleles of the genes encoding Utx and Jmjd3 (Kdm6a and Kdm6b, respectively) were deleted in double positive (DP) thymocytes carrying a CD4 Cre transgene. Genome-wide H3K27Me3 ChipSeq was performed on (i) pre-selection (CD69lo) DP thymocytes from wild-type mice carrying an endogenous polyclonal TCR repertoire, (ii) mature (TCRhi CD24lo) CD4 SP thymocytes from wild type (Wt), Jmjd3KO, UtxKO and dKO mice carrying an endogenous polyclonal TCR repertoire and (iii) mature (Va2hi CD24lo) CD4 SP thymocytes from wild type and dKO mice carrying the OTII TCR transgene.
2015-09-02 | E-GEOD-70795 | biostudies-arrayexpress
Project description:Dr. Jameson's research focus is on development and regulation of lymphocytes, especially T cells. Recent work has suggested that differential glycosylation effects the sensitivity of the T cell receptors and its coreceptors, suggesting that regulation of glycosylation may be a critical element in controlling T cell development, survival and functional activity. Determination of how glycosylation enzymes/substrates change in gene expression during development of mouse CD8 T cells. Highly purified pre-selection CD4+8+ thymocytes (using transgenic/knockout mice in our colony) are compared to mature CD8 T cells from the lymph node. The goal is to build on data suggesting that this developmental step involves regulated expression of sialyltransferases (and/or neuraminidases). Highly purified pre-selection CD4+8+ thymocytes (using transgenic/knockout mice in our colony) are compared to mature CD8 T cells from the lymph node. Pre-selection CD4+8+ (DP) thymocytes were sorted from TCRa-/- thymi. Post-selection (post-positive selection) DP thymocytes came from an OT-I TCR transgenic mouse. Naïve (CD44lo) CD8 T cells from lymph node of OT-I mice were used as naïve CD8 T cells. For activated cells, naïve OT-I T cells were activated for 48 hours in vitro with cognate antigen (SIINFEKL peptide/Kb) (displayed on cell sized latex beads) in the presence of IL-2 and IL-12.
2010-12-11 | E-GEOD-26012 | biostudies-arrayexpress
Project description:CD4 and CD8 T cells are vital components of the immune system. According to the kinetic signaling model, commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. We found histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as its deletion leads to the generation of only CD8SP thymocytes. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage. Analysis of histone acetylation and RNA-seq reveals HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. In addition, HDAC3-deficient DP thymocytes have increased IL-21R expression and STAT5 activation. As a result, HDAC3 is required to restrain cytokine signaling in DP thymocytes and is required for the generation of CD4 T cells.
2019-01-20 | GSE109529 | GEO
Project description:CD4 and CD8 T cells are vital components of the immune system. According to the kinetic signaling model, commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. We found histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as its deletion leads to the generation of only CD8SP thymocytes. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage. Analysis of histone acetylation and RNA-seq reveals HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. In addition, HDAC3-deficient DP thymocytes have increased IL-21R expression and STAT5 activation. As a result, HDAC3 is required to restrain cytokine signaling in DP thymocytes and is required for the generation of CD4 T cells.
2019-01-20 | GSE109530 | GEO
Project description:In mice and humans, an immature CD4-CD8- double negative (DN) thymocyte subset expresses early, mature αβTCR. These early αβTCR+ DN (EADN) cells are susceptible to leukemogenesis in both species. Using the OT-1 TCR transgenic system to model EADN-stage αβ TCR expression, we found that EADN cells show coreceptor-independent reactivity to MHC, and their TCR:MHC dependent signals can drive T-ALL transformation. We generated gene expression data from OT-1 leukemic cells and assessed their developmental stage by comparing to wild-type thymocyte subsets.
2022-06-28 | GSE180556 | GEO
Project description:Conditional knock out of Brd1(bromodomain containing 1) in muse developmental T cells (CD4CD8DP, CD4SP and CD8SP) by intercrossing with Tie2-Cre Conditional knock out of Brd1(bromodomain containing 1) in muse MHC class l restricted T cells (CD8SP) by intercrossing with Tie2-Cre and OT-l Developmental T cells (defined by surface markers: CD4, CD8 and TCR?) derived from control (Tie2-Cre) or Brd1 conditional knock out (Brd1flox/flox, Tie2-Cre) thymocytes were isolated by fluorescence activated cell sorting (FACS) and subjected to a microarray analysis. CD8SP T cells were also isolated from control (Tie2-Cre, OT-l) or Brd1 conditional knock out (Brd1flox/flox, Tie2-Cre, OT-l) thymocytes intercrossed with OT-l.
2014-05-24 | E-GEOD-48797 | biostudies-arrayexpress
Project description:The TAL1/SCL and LMO1 oncogenic transcription factors establish a pre-leukemic state by reprogramming thymocytes into self-renewing pre-leukemic stem cells (pre-LSCs). Pre-TCR signaling accelerates the progression to T-cell acute lymphoblastic leukemia (T-ALL). To directly address the importance of pre-TCR signaling in driving progression to T-ALL, we leverage on Cd3-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated. In the absence of pre-TCR signaling in Cd3ε-deficient SCL-LMO1 transgenic mice, T-ALL onset is delayed by 150 days. Despite the absence of pre-TCR/CD3 signaling in these mice, we show that leukemic thymocytes exhibit the gene expression profiles of thymocytes that have undergone β-selection, i.e. exhibiting a re-activation of pre-TCR-driven proliferation signature, and a down regulation of HEB/TCF12 target genes. Lastly, monoallelic deletion of Heb is sufficient to accelerate T-ALL onset in Cd3ε-deficient SCL-LMO1 transgenic mice. Together, these results underscore the role of HEB/TCF12 as a tumor suppressor in T-ALL.
2022-03-27 | GSE198506 | GEO
Project description:To understand the role of the H3K27me3 demethylases, UTX and JMJD3, in B cell differentiation. CUT&Tag for H3K27me3 was performed on CreCtrl and dKO (UTX and JMJD3-deficient) PC at day three post in vivo stimulation with LPS.
2022-02-01 | GSE185098 | GEO